The class of compounds known as pyridoazepines have been identified as biologically active and useful in the treatment of various physiological disorders. (see, e.g., U.S. Pat. Nos. 4,177,275 and 4,936,121 and Yamamoto et al, Heterocycles, 11, 267-73, 1978). For example, pyridoazepine compounds have been shown to have antihistamine and antiserotonin activity.
Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system and enterochromaffin cells of the gastrointestinal tract. The most common drug therapies involving 5-HT include SSRIs (serotonin reuptake inhibitors), MAOIs (monoamine oxidase inhibitors) and tricyclic antidepressants. SSRIs, considered the safest of the therapies, still possesses potential side effects including insomnia, nausea, diminished sexual interest and weight gain. (see, e.g., Hirschfeld, R., J. Clin. Psychiatry, 64 [suppl 18], 20-24, 2003).
Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in health and in psychiatric disorders. 5-HT has been implicated in the regulation of feeding behavior for some time. 5-HT appears to work by inducing a feeling of fullness or satiety so eating stops earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT2C receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5-HT2C receptor ligand (e.g., a 5-HT2C receptor agonist) can be a more effective and safe anti-obesity agent. Also, 5-HT2C knockout mice are overweight with cognitive impairment and susceptibility to seizure.
It is believed that 5-HT2C may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, 5-HT2C receptor ligands (e.g., 5-HT2C receptor agonists) can have anti-panic properties, and properties useful for the treatment of sexual dysfunction.
In sum, the 5-HT2C receptor is a validated and well-accepted receptor target for the treatment of obesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT2C receptor ligands (e.g., 5-HT2C receptor agonists) which safely decrease food intake and body weight.